Fast dissolving orally consumable films

ABSTRACT

Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-forming polymer such as pullulan. Edible films are disclosed that include pullulan and antimicrobially effective amounts of the essential oils thymol, methyl salicylate, eucalyptol and menthol. The edible films are effective at killing the plaque-producing germs that cause dental plaque, gingivitis and bad breath. The film can also contain pharmaceutically active agents. Methods for producing the films are also disclosed.

FIELD OF THE INVENTION

[0001] This invention relates to fast dissolving orally consumablefilms. The films are used to deliver breath deodorizing agents,antimicrobial agents and salivary stimulants to the oral cavity. Thefilms can also be used to deliver pharmaceutically active agents.

BACKGROUND OF THE INVENTION

[0002] In a more perfect world, people would thoroughly cleanse theirmouths after each meal as part of their routine oral hygienic practices.Unfortunately, several factors conspire to prevent widespread compliancewith this basic requirement of a good oral cleaning regimen.

[0003] Oral cleansing can be difficult or inconvenient at times,depending on the nature of the cleansing and the situation in which thecleansing must occur. Brushing, flossing, cleaning your tongue andgargling using a variety of devices and compositions well-suited for theprivacy of one's home are common oral care practices. However, thedevices and compositions used in oral cleansing practices are lessconvenient to use away from home, where bathroom facilities might bescarce, unavailable or unsanitary.

[0004] As brushing, flossing, cleaning your tongue and gargling inpublic are not considered to be socially acceptable behaviors in many,if not all cultures, a variety of less obtrusive oral cleansing productshave been developed. These include breath-freshening gums and lozenges.Although gums and lozenges have been formulated to achieve a variety ofbeneficial effects, they are not always socially acceptable. Forexample, gum is expressly banned from certain institutions, such asschools as well as in certain countries, such as Singapore. Gums andmints are used over extended periods of time, and they require an amountof sucking or chewing action on the part of the consumer, which can bedistracting, tedious and undesirable.

[0005] Another portable oral cleansing product is a mouthspray. Like amouthwash, a mouthspray can provide the consumer with a quick burst ofstrong breath-freshening action, which might be overwhelming in anextended-consumption product like gum or lozenges. On the other hand,mouthsprays are obtrusive. Spraying a mouthspray typically generates anoise, which undesirably draws the attention of the public to theconsumer. Moreover, mouthsprays are typically packaged in relativelyexpensive and complex metal canisters, which can clog in use and are notenvironmentally friendly. Furthermore, misdirecting the spray not onlywastes the product, but can result in irritated eyes, a sticky faceand/or stained clothing.

[0006] It has been proposed to use an edible film as a vehicle forunobtrusively delivering breath-freshening agents. See JP 5-236885. ThisJapanese patent application does not, however, teach the inclusion ofantimicrobial agents in the film, using the film to decrease the amountof undesirable bacteria within the oral cavity, or stimulating saliva.Furthermore, this patent application does not disclose employing itsfilm for purposes other than breath freshening or within cavities otherthan the mouth.

[0007] U.S. Pat. No. 5,518,902 to Ozaki et al. (Hayashibara) discloseshigh pullulan content products, such as edible films, dentifrices andpharmaceuticals (column 3, lines 44-56 and Example B-8). The productscan include a variety of ingredients in addition to pullulan, such asother polysaccharides, polyhydric alcohols, antiseptics andflavor-imparting agents (column 4, line 58 to column 5, line 11). Noneof the essential oils, such as thymol, eucalyptol, methyl salicylate ormenthol, are mentioned as suitable ingredients.

[0008] U.S. Pat. No. 5,411,945 to Ozaki et al. (Hayashibara) discloses apullulan binder and products produced therewith, including edible films(Example B-2). The products can include a variety of ingredients inaddition to pullulan, such as other polysaccharides, antibacterialagents, flavor-imparting agents and pharmaceutically active substances(column 4, lines 5-15). None of the essential oils are mentioned assuitable ingredients.

[0009] U.S. Pat. No. 4,851,394 to Kubodera disclosesglucomannan/polyhydric alcohol edible films, which can comprise pullulan(column 3, line 59 to column 4, line 21). The films are contrasted withexisting pullulan-based films, which are said to lack resistance towater (column 1, lines 40-44). None of the essential oils are mentionedas suitable ingredients.

[0010] U.S. Pat. No. 3,784,390 Hijiya et al. discloses pullulan filmsand their use in coating and packing materials for foods,pharmaceuticals and other oxygen sensitive materials. All of theexamples in this patent teach mixing pullulan in hot water.

[0011] U.S. Pat. No. 4,623,394 Nakamura et al. discloses a graduallydisintegrable molded article that can be a film made with pullulan. Thearticles contain a particular heteromannan, which can be locust beangum.

[0012] U.S. Pat. No. 4,562,020 Hijiya et al. discloses a process forproducing a self-supporting film of a glucan, which can be pullulan.

[0013] Japanese Patent Document JP5-1198 discloses films made ofpolyvinyl alcohol and at least one of carrageenan, water-solublecellulose alpha-starch and water-soluble polysaccharides.

[0014] WO 99/17753 discloses rapidly dissolving films for delivery ofdrugs to be adsorbed in the digestive tract.

[0015] WO 98/26780 discloses a flat, foil, paper or wafer typepresentation for the application and release of active substances in thebuccal cavity. The specific active ingredient disclosed in WO 98/26780is buprenorphine.

[0016] WO 98/20862 discloses a film for use in the oral cavity that cancontain a cosmetic or pharmaceutical active substance.

[0017] WO 98/26763 discloses a flat, foil, paper or wafer likepresentation for release of active substances into the buccal cavity.The particular active disclosed is apomorphine.

[0018] Despite the existence of rapidly dissolving orally consumablefilms in the prior art, there is still room for improvement in suchfilms, and in processes for making them.

[0019] All references cited herein are incorporated herein by referencein their entireties.

SUMMARY OF THE INVENTION

[0020] The invention provides a physiologically acceptable film, whichis particularly well adapted to adhere to and rapidly dissolve in themouth of a consumer. In a first embodiment of the invention, the filmdelivers at least one oral care agent, such as antimicrobial agents andsalivary stimulants. The antimicrobial agents are effective againstgerms that cause halitosis, dental plaque, and gingivitis. The salivarystimulants are effective against the condition known as xerostomia ordry mouth. Additionally, the oral care films are a breath freshenereffective against oral malodor. The film former used to make the filmsaccording to the present invention entraps the oral care agents in theoral cavity to provide extended efficacy.

[0021] In a second embodiment of the invention, the rapidly dissolvablefilm acts as a vehicle for administering a pharmaceutically active agentorally, through a mucous membrane or an open wound of a patient.

[0022] The invention is also directed to a method for producing asupple, non-self-adhering film especially suitable for oral delivery.The method comprises mixing a film forming agent and at least onestabilizing agent to provide a film-forming mixture; dissolvingwater-soluble ingredients in water to provide an aqueous solution;combining the film-forming mixture and the aqueous solution to provide ahydrated polymer gel; mixing oils to form an oil mixture; adding the oilmixture to the hydrated polymer gel and mixing to provide a uniformemulsified gel; casting the uniform gel on a substrate; and drying thecast gel to provide a film.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]FIG. 1 is a photograph of an agar plate spread with Streptococcusmutans, ATCC 25175, and exposed to a film according to the presentinvention that contains 0.391 mg of essential oils.

[0024]FIG. 2 is a photograph of an agar plate spread with Streptococcusmutans, ATCC 25175, and exposed to drops of an essential oil mixturecontaining 0.391 mg of essential oils per drop.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0025] Description of Oral Care Film Compositions

[0026] The first embodiment of the invention is a physiologicallyacceptable film that is particularly well adapted to adhere to anddissolve in a mouth of a consumer to deliver an antimicrobial agent thatkills germs that cause halitosis, dental plaque and gingivitis. Thus,the film can be an effective tool in the prevention and treatment ofhalitosis, dental plaque accumulation, dental tartar accumulation andgingivitis. This film preferably comprises pullulan, thymol, methylsalicylate, eucalyptol and menthol.

[0027] LISTERINE® brand mouthwash is, perhaps, the most well-knownexample of an antiseptic oral composition that has proven effective inkilling microbes in the oral cavity that are responsible for plaque,gingivitis and bad breath. LISTERINE® brand mouthwash achieves itsantimicrobial effect through a combination of essential oils thatpenetrate and kill the microorganisms. These essential oils includeprecisely balanced amounts of thymol, methyl salicylate, menthol andeucalyptol (hereinafter “the essential oils”) in a hydro alcoholicsolution. Many bad breath bacteria live in pits or fissure on thesurface of the tongue. Listerine® Antiseptic mouthwash reduces badbreath because of high concentrations of antimicrobial agents in aliquid medium that can easily penetrate into these pits and fissures.This would not be possible with a solid dosage form containing lowamounts of these antimicrobial ingredients. However, the preferredconsumable film of the invention captures a significant portion of thehygienic benefits and the consumer appeal of LISTERINE® brand mouthwash,in a more portable and unobtrusively consumed form.

[0028] It was a significant challenge to maintain the essential oilinteraction and relatively high oil content of LISTERINE® brandmouthwash in a film. However, the inventors have overcome this challengein providing the film of the invention.

[0029] A further aspect of this invention is that while the amounts ofLISTERINE® essential oils are relatively high for incorporation in afilm, the film according to the present invention still delivers a lowertotal amount of essential oils per unit dose when compared to that ofLISTERINE® mouthwash. Yet the film suprisingly provides antimicrobialefficacy in the oral cavity. The inventors theorize that the preferredfilm forming ingredient, pullulan, forms a thin layer on the oralsurfaces entrapping the small amount of essential oils which are capableof penetrating into the pits and fissures of the oral cavity to providesustained antimicrobial efficacy.

[0030] Although the inventors are presently unaware of any otherbreath-freshening consumable film that provides antimicrobial efficacy,they are aware of a consumable film disclosed in JP 5-236885, which issaid to possess breath-freshening activity, but is not described aspossessing any ingredients having significant antimicrobial activity.Moreover, JP 5-236885 teaches that its film should contain flavor andextract in amounts of 5 to 7 wt %, with the flavor being added as an oil(the essential oils are not disclosed), whereas the film of theinvention preferably has an oil content of at least about 10 wt %, morepreferably about 15 wt % to about 30 wt %, most preferably about 15 wt %to about 25 wt %. Except as otherwise noted in the examples, the amountsof oils and other ingredients in the film are wt% after the filmformulation has been dried to create the film.

[0031] The amounts of the specific essential oils used in the filmcompositions can vary as long as they are in amounts sufficient toprovide antimicrobial efficacy. Generally the amount of thymol, methylsalicylate and eucalyptol is from about 0.01 to about 4 wt % of the filmcomposition, preferably about 0.50 to about 3.0 wt % and even morepreferably from about 0.70 to about 2.0 wt % of the film. Menthol can beadded from about 0.01 to about 15 wt % of the composition, preferablyabout 2.0 to about 10 wt % and even more preferably from about 3 toabout 9 wt % of the film. The amounts added can be readily determined tothose skilled in the art and can exceed these amounts as long as thetotal oil content does not create sticking or other processing problems.In certain embodiments, the essential oils are combined in amountssynergistically effective to kill the plaque-producing germs that causedental plaque, gingivitis and bad breath.

[0032] A major difficulty in formulating a film having such a relativelyhigh oil content is that simply increasing the amount of oil in the filmwithout determining the precise proportions of the many otheringredients typically results in a film that is too moist and thereforedifficult to handle or process. The inventors have discovered how toprovide a high oil content film that is moist enough so that it is notbrittle, but is not so moist that it feels undesirably slimy orsignificantly adheres to adjacent films. Thus, a non-self-adhering filmaccording to the invention can be stored in contact with another suchfilm (e.g., in a stack), or can be wound about itself (e.g., around aspool), without having to place a non-stick agent (e.g., a plastic film,paper or other support) between adjacent portions of film.

[0033] The film-forming agent used in the films according to the presentinvention can be selected from the group consisting of pullulan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinylalcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanthgum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl polymer, amylose, highamylose starch, hydroxypropylated high amylose starch, dextrin, pectin,chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soyprotein isolate, whey protein isolate, casein and mixtures thereof. Apreferred film former is pullulan, in amounts ranging from about 0.01 toabout 99 wt %, preferably about 30 to about 80 wt %, more preferablyfrom about 45 to about 70 wt % of the film and even more preferably fromabout 60 to about 65 wt % of the film.

[0034] The film of the invention preferably comprises pullulan as afilm-forming agent and the essential oils as antimicrobial/flavoringagents, and can further comprise water, additional antimicrobial agents,additional film-forming agents, plasticizing agents, additionalflavoring agents, sulfur precipitating agents, saliva stimulatingagents, cooling agents, surfactants, stabilizing agents, emulsifyingagents, thickening agents, binding agents, coloring agents, sweeteners,fragrances, and the like.

[0035] Due to the relatively high oil content in the oral care film, itis preferable to avoid substantial amounts of humectant in the film (andmore preferable to have no humectant in the film), so as to avoidproducing an overly moist, self-adhering film. In particular, it ispreferred to formulate the film with a plasticizing agent other thanglycerin, which is also a humectant, and with a sweetener other thansorbitol, which is a mild humectant.

[0036] Sulfur precipitating agents that reduce oral malodor can also beadded to the oral care films according to the present invention. Theseagents bind with, and inactivate, the volatile sulfur compounds thatcause a large percentage of oral malodor. Sulfur precipitating agentsuseful in the present invention include metal salts such as copper saltsand zinc salts. Preferred salts include copper gluconate, zinc citrateand zinc gluconate. The amount of sulfur precipitating agent is fromabout 0.01 to about 2 wt %, preferably about 0.15 wt % to about 1.5 wt%, even more preferably about 0.25 wt % to about 1.0 wt % of the film.

[0037] Saliva stimulating agents can also be added to the oral carefilms according to the present invention. Useful saliva stimulatingagents are those disclosed in U.S. Pat. No. 4,820,506, which isincorporated by reference herein in its entirety. Saliva stimulatingagents include food acids such as citric, lactic, malic, succinic,ascorbic, adipic, fumaric and tartaric acids. Preferred food acids arecitric, malic and ascorbic acids. The amount of saliva stimulatingagents in the film is from about 0.01 to about 12 wt %, preferably about1 wt % to about 10 wt %, even more preferably about 2.5 wt % to about 6wt %.

[0038] Preferred plasticizing agents include triacetin in amountsranging from about 0 to about 20 wt %, preferably about 0 to about 2 wt%. Other suitable plasticizing agents include monoacetin and diacetin.

[0039] Preferred cooling agents include monomenthyl succinate, inamounts ranging from about 0.001 to about 2.0 wt %, preferably about 0.2to about 0.4 wt %. A monomenthyl succinate containing cooling agent isavailable from Mane, Inc. Other suitable cooling agents include WS3,WS23, Ultracool II and the like.

[0040] Preferred surfactants include mono and diglycerides of fattyacids and polyoxyethylene sorbitol esters, such as, Atmos 300 andPolysorbate 80. The surfactant can be added in amounts ranging fromabout 0.5 to about 15 wt %, preferably about 1 to about 5 wt % of thefilm. Other suitable surfactants include pluronic acid, sodium laurylsulfate, and the like.

[0041] Preferred stabilizing agents include xanthan gum, locust bean gumand carrageenan, in amounts ranging from about 0 to about 10 wt %,preferably about 0.1 to about 2 wt % of the film. Other suitablestabilizing agents include guar gum and the like.

[0042] Preferred emulsifying agents include triethanolamine stearate,quaternary ammonium compounds, acacia, gelatin, lecithin, bentonite,veegum, and the like, in amounts ranging from about 0 to about 5 wt %,preferably about 0.01 to about 0.7 wt % of the film.

[0043] Preferred thickening agents include methylcellulose, carboxylmethylcellulose, and the like, in amounts ranging from about 0 to about20 wt %, preferably about 0.01 to about 5 wt %.

[0044] Preferred binding agents include starch, in amounts ranging fromabout 0 to about 10 wt %, preferably about 0.01 to about 2 wt % of thefilm.

[0045] Suitable sweeteners that can be included are those well known inthe art, including both natural and artificial sweeteners. Suitablesweeteners include, e.g.:

[0046] A. water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose(dextrose), mannose, galactose, fructose (levulose), sucrose (sugar),maltose, invert sugar (a mixture of fructose and glucose derived fromsucrose), partially hydrolyzed starch, corn syrup solids,dihydrochalcones, monellin, steviosides, and glycyrrhizin;

[0047] B. water-soluble artificial sweeteners such as the solublesaccharin salts, i.e., sodium or calcium saccharin salts, cyclamatesalts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2, 2-dioxide, the potassium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K),the free acid form of saccharin, and the like;

[0048] C. dipeptide based sweeteners, such as L-aspartic acid derivedsweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame)and materials described in U.S. Pat. No. 3,492,131,L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate, methyl esters of L-aspartyl-L-phenylglycerin andL-aspartyl-L-2,5,dihydrophenyl-glycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexyen)-alanine, and the like;

[0049] D. water-soluble sweeteners derived from naturally occurringwater-soluble sweeteners, such as a chlorinated derivative of ordinarysugar (sucrose), known, for example, under the product description ofsucralose; and

[0050] E. protein based sweeteners such as thaumatoccous danielli(Thaumatin I and II).

[0051] In general, an effective amount of auxiliary sweetener isutilized to provide the level of sweetness desired for a particularcomposition, and this amount will vary with the sweetener selected. Thisamount will normally be 0.01 % to about 10 % by weight of thecomposition when using an easily extractable sweetener. Thewater-soluble sweeteners described in category A above, are usually usedin amounts of about 0.01 to about 10 wt %, and preferably in amounts ofabout 2 to about 5 wt %. Some of the sweeteners in category A (e.g.,glycyrrhizin) can be used in amounts set forth for categories B-E belowdue to the sweeteners' known sweetening ability. In contrast, thesweeteners described in categories B-E are generally used in amounts ofabout 0.01 to about 10 wt %, with about 2 to about 8 wt % beingpreferred and about 3 to about 6 wt % being most preferred. Theseamounts may be used to achieve a desired level of sweetness independentfrom the flavor level achieved from any optional flavor oils used. Ofcourse, sweeteners need not be added to films intended for non-oraladministration.

[0052] The flavorings that can be used include those known to theskilled artisan, such as natural and artificial flavors. Theseflavorings may be chosen from synthetic flavor oils and flavoringaromatics, and/or oils, oleo resins and extracts derived from plants,leaves, flowers, fruits and so forth, and combinations thereof.Representative flavor oils include: spearmint oil, cinnamon oil,peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil ofnutmeg, oil of sage, and oil of bitter almonds. Also useful areartificial, natural or synthetic fruit flavors such as vanilla,chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape,lime and grapefruit and fruit essences including apple, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.These flavorings can be used individually or in admixture. Commonly usedflavors include mints such as peppermint, artificial vanilla, cinnamonderivatives, and various fruit flavors, whether employed individually orin admixture. Flavorings such as aldehydes and esters including cinnamylacetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate,eugenyl formate, p-methylanisole, and so forth may also be used.Generally, any flavoring or food additive, such as those described inChemicals Used in Food Processing, publication 1274 by the NationalAcademy of Sciences, pages 63-258, may be used. Further examples ofaldehyde flavorings include, but are not limited to acetaldehyde(apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon);citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral(lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream);heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla,cream); alpha-amyl cinnamaldehyde (spicy fruity flavors); butyraldehyde(butter, cheese); valeraldehyde (butter, cheese); citronellal (modifies,many types); decanal (citrus fruits); aldehyde is C-8 (citrus fruits);aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethylbutyraldehyde (berry fruits); hexenal, i.e. trans-2 (berry fruits);tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2,6-dimethyl-5-heptenal, i.e. melonal (melon); 2-6-dimethyloctanal (green fruit); and2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof; and thelike.

[0053] The amount of flavoring employed is normally a matter ofpreference subject to such factors as flavor type, individual flavor,and strength desired. Thus, the amount may be varied in order to obtainthe result desired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. In general, amounts of about 0.1 to about 30 wt % areuseable with amounts of about 2 to about 25 wt % being preferred andamounts from about 8 to about 10 wt % are more preferred.

[0054] The compositions of this invention can also contain coloringagents or colorants. The coloring agents are used in amounts effectiveto produce the desired color. The coloring agents useful in the presentinvention, include pigments such as titanium dioxide, which may beincorporated in amounts of up to about 5 wt %, and preferably less thanabout 1 wt %. Colorants can also include natural food colors and dyessuitable for food, drug and cosmetic applications. These colorants areknown as FD&C dyes and lakes. The materials acceptable for the foregoingspectrum of use are preferably water-soluble, and include FD&C Blue No.2, which is the disodium salt of 5,5-indigotindisulfonic acid.Similarly, the dye known as Green No. 3 comprises a triphenylmethane dyeand is the monosodium salt of 4-[4-N-ethyl-p-sulfobenzylamino)diphenyl-methylene]-[1-N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclo-hexadienimine]. A full recitation of all FD&C and D&Cdyes and their corresponding chemical structures may be found in theKirk-Othmer Encyclopedia of Chemical Technology, Volume 5, Pages857-884, which text is accordingly incorporated herein by reference.

[0055] Antimicrobial Efficacy of Oral Care Films

[0056] The preferred embodiment of the oral care film compositionaccording to the present invention contains the essential oils used inListerine® mouthwash to provide antimicrobial efficacy. The films areshaped and sized to be placed in the oral cavity. The film adheres to asurface in the mouth, usually the roof of the mouth or the tongue, andquickly dissolves. The amount of essential oils in one individual filmthat is a preferred size for placing in the mouth is significantly lowerthan that in the recommended amount, 20 ml, of Listerine® mouthwash.

[0057] In a preferred formula according to the present invention, theamount of thymol and eucalyptol in the film is about 70 times less thanin the mouthwash. The amount of methyl salicylate in the film is about46 times less than in the mouthwash. The amount of menthol in the filmis about 2.8 times less than in the mouthwash. These figures are basedon comparing a 20 ml dose of liquid mouthwash with a 0.0358 gram film.

[0058] The inventors have unexpectedly found that the film providessustained antimicrobial efficacy at these low amounts of oils. Theinventors believe that the efficacy of the essential oils is enhanced bythe creation of a layer of pullulan in the oral cavity that holds theessential oils. This is unexpected because pullulan is water-soluble andthe film dissolves very quickly.

[0059] The extended antimicrobial activity is shown in the followingexperiments.

[0060] The purpose of these experiments was to determine theantibacterial efficacy of an application of a breath film on tonguemalodor microorganisms thirty, sixty or ninety minutes after use. Thethirty minute study also tested the efficacy of using two films.Subjects' baseline oral malodor microbial recoverable counts weredetermined by plating the microorganisms recovered from a tongue swab ona selective agar medium. The test product was dispensed and subjectsdissolved one or two breath films on their tongue. Subjects remained onthe premises and returned for a second tongue swab thirty, sixty orninety minutes after placement of the test product on their tongue.After a forty-eight hour washout period, subjects returned for a notreatment control.

[0061] The thirty minute single film use group showed a reduction inmean log malodor microbial counts compared to the control group. Thedata was borderline statistically significant (p=0.052). The differencebetween the one film group and the no treatment control grouprepresented a 42.7% reduction in malodor microbial colony counts.

[0062] Statistically significant malodor microbial reduction was alsoobserved with the two film use group. A 79.6% reduction in malodormicrobial colony counts was obtained (p<0.001).

[0063] Statistically significant malodor microbial reduction wasobserved sixty minutes after use of a single breath film. A 69.8%reduction in malodor microbial colony counts was obtained (p=0.002).

[0064] Significant malodor reduction was also observed ninety minutesafter use of a single breath film. A 69.1% reduction in malodormicrobial colony counts was obtained (p=0.006).

[0065] The data from these studies support the following conclusions:(1) Pullulan polymer-based breath film containing essential oils is aneffective antibacterial composition against oral malodor causingbacteria and (2) significant in vivo bacterial reductions were achievedat thirty, sixty and ninety minutes post use.

[0066] Experimental Procedures

[0067] The procedures used in these antimicrobial studies were asfollows. The subject were required to refrain from all oral hygieneprocedures (e.g., toothbrushing, oral lavage) eating or drinking anyfood, beverage or confectionery products from midnight prior to thestudy and until the study was completed on each test day. Subjectsrefrained from smoking on mornings prior to the odor evaluations.

[0068] In vivo Germ Kill Assay

[0069] 1. Materials

[0070] Test tubes containing 10 ml of sterile 0.01% peptone

[0071] Sterile Swabs

[0072] OOPS III Agar (B.-F. Turng, G. E. Minah, and W. A. Falkler.Development of an Agar Medium for Detection of Oral H₂S-producingOrganisms. J Dent Res 76 IADR Abstracts 1997.): Columbia Agar Base(Catalogue #DF0792-17-3) 44 grams Distilled Water 1 liter LeadAcetate^(a) (Sigma L3396) 0.2 grams Hemin Solution^(b) (Sigma H-1652) 2ml Glutathione^(c) (Sigma G4251) 1.2 grams

[0073] Forty-four grams of Columbia Blood Agar Base was suspended in 1liter distilled water and boiled to dissolve completely. The media wassterilized at 121-124° C. for 15 minutes.

[0074]^(a) Dissolved 0.2 grams of lead acetate in 1 ml of distilled H₂Oand filter sterilized. Added after autoclaving the base media.

[0075]^(b) Dissolved 50 mg of hemin in 1 ml of 1N NaOH; qs'd to 100 mlwith distilled H₂O. Filter sterilized. Added 2 ml per liter of OOPS IIIafter autoclaving base media.

[0076]^(c) Dissolved 1.2 grams of glutathione in 10 ml of distilled H₂O.Filter sterilized. Added after autoclaving base media.

[0077] 2. Procedure

[0078] a. All media were prereduced in an anaerobic chamber overnight.Plates were loosely wrapped in plastic bags to prevent excessive drying.

[0079] b. Panelists refrained from oral hygiene, eating and drinkingfrom midnight prior to the assay and until the assay was complete.Twelve panelists were used for the sixty and ninety minute experiments.Eighteen panelists were used for the thirty minute experiments.

[0080] c. Each panelist swabbed the right side of his tongue by placingthe swab at the midpoint of the tongue and swiping forward to the tip.The swab was placed in a tube of peptone.

[0081] d. The panelist received a film treatment, either a single ordouble film. Panelists placed the breath film on the left side of theirtongue covering the tongue from the midpoint to the tip and allowed thefilm to dissolve with the mouth slightly open for thirty seconds toprevent the film from sticking to the palate.

[0082] e. After thirty or sixty minutes, panelists swabbed the left sideof the tongue by placing the swab at the midpoint of the tongue andswiping forward to the tip. The swab was placed in a tube of peptone.

[0083] f. The tubes of peptone were vortexed vigorously for 10 seconds,and serial dilutions were made. The 10⁻⁴ dilution was plated induplicate on OOPS III Agar using a Spiral Biotech Autoplate 4000(Bethesda, Md.). All plates were identified with the subject's initials,assay date, sampling time station, and replicate number.

[0084] g. The plates were incubated in an anaerobic chamber at 35-37° C.for 7 days to permit full development of colonies without overgrowth.

[0085] h. After a 48 hour wash out period, panelists returned for the notreatment control. No film was applied, and steps (e) through (g) werefollowed as described above.

[0086] i. After a 48 hour wash out period, the sixty minute panelistsreturned for another single film application. Steps (a) through (h) werefollowed, with the exception that panelists returned after 90 min instep e.

[0087] j. The dark-pigmented colonies (H₂S-producing organisms) werecounted as whole plate counts by hand under appropriate magnification orby Segment counts using a Spiral Biotech counting template. Theappropriate code was entered on the data sheet to permit interpretationof the counts. The CFU's counted were converted to CFU/ml by dividing bythe appropriate exponential volume constant listed in Table A andmultiplying by 1000. This value was then multiplied by the dilutionfactor of the plate (10⁴). TABLE A Exponential Volume Constants forSegment Pairs Last Counted Segment Exponential Volume Constant  8 1.214 9 2.968 10 5.500 11 9.157 12 14.482 13 25.015 Total Plate 50.030

[0088] The film used in the in vivo germ kill tests was Example 19 asdescribed in Table 2. The films used in the study were approximately 22mm×32 mm, between about 0.0013 and 0.0015 inches thick and weighedbetween about 35 to about 37 mg.

[0089] The enhanced activity of the essential oil containing pullulanfilm is also shown in FIGS. 1 and 2. FIG. 1 is a photograph of an agarplate spread with Streptococcus mutans, ATCC # 25175, to which a pieceof an essential oil pullulan film according to the present invention wasadded. The piece of film delivered approximately 0.391 mg of essentialoils using Example 15 listed below.

[0090]FIG. 2 is a photograph of an agar plate spread with Streptococcusmutans, ATCC # 25175 to which drops of essential oils have been added.The drops were 148 μl in volume and contained 0.391 mg of essentialoils. The percentages of each essential oil in the drop are 2.200%menthol, 0.186% eucalyptol, 0.186% methyl salicylate and 0.1300% thymolin a hydro alcohol solution.

[0091] The area or zone of inhibition around the film in FIG. 1 is muchlarger than the dimensions of the film. This is due to the presence ofpullulan because the oils in the pullulan film were spread by thepullulan, diffused outward and did not wash away after repeated rinses.In contrast, the essential oils in FIG. 2 did not diff-use away from thedroplet, remained as a circle and easily washed off after 1-2 rinses.This shows that the antimicrobial efficacy of the essential oils isenhanced by the presence of pullulan.

[0092] Methods For Preparing Essential Oil Containing Films

[0093] Methods for preparing films according to the invention arecapable of encapsulating the oil ingredients within the film-formingmatrix and maintaining the integrity of the film, even when the filmcontains oils in amounts of 10 wt % or more.

[0094] In certain methods for preparing films according to theinvention, the film-forming ingredients are mixed and hydrated withwater separately from the water-soluble ingredients, which are mixed inaqueous solution separately from the organic ingredients andsurfactants. In these methods, the final formulation is preferablyproduced by mixing the film-forming phase with the aqueous phase, thenmixing in the organic phase, which includes surfactants, such asPolysorbate 80 and Atmos 300. This mass is mixed until emulsified. Inother embodiments, the aqueous and film forming phases are combined intoa single phase by dissolving the water soluble ingredients in the waterand then adding the gums to hydrate. The organic phase is then added tothis single aqueous phase.

[0095] The resulting formulation is cast on a suitable substrate anddried to form a film. The film is preferably air-dried or dried underwarm air and cut to a desired dimension, packaged and stored. The filmcan contain from about 0.1% to about 10 wt % moisture, preferably fromabout 3% to about 8 wt % moisture, even more preferably from about 4 toabout 7 wt % moisture.

[0096] The film-forming phase can include pullulan and stabilizingagents such as xanthan gum, locust bean gum and carrageenan. Theseingredients are mixed and then hydrated in water for about 30 to about48 hours to form a gel. The water is preferably heated to a temperatureof about 25 to about 45° C. to promote hydration. The amount of water isabout 40 to 80% of the gel. The resulting hydrated gel is then chilledto a temperature of about 20 to about 30° C. for about 1 to about 48hours. The water is preferably deionized.

[0097] The aqueous phase can include ingredients such as coloringagent(s), copper gluconate and sweetener. The water is preferablydeionized and the amount of water used is about 5 to about 80 wt % ofthe final gel mixture.

[0098] If sodium saccharin and copper gluconate are both ingredients inthe formulation, it is preferable to dissolve them separately insolution to avoid precipitation.

[0099] In a preferred method of producing essential oil containing filmsaccording to the invention, it is possible to hydrate the film-formingingredients and combine all of the ingredients without heating. Thepreferred method of producing films comprises dissolving thewater-soluble ingredients in water to form an aqueous mixture; mixingthe film-forming ingredients in powder form to form a powder mixture;adding the powder mixture to the aqueous mixture to form a hydratedpolymer gel; stirring the hydrated polymer at room temperature for about30 minutes to about 48 hours; mixing the cooling agent, thymol andmenthol in the flavor oil to form an oil mixture; adding methylsalicylate; eucalyptol and surfactants to the oil mixture; adding theoil mixture to the hydrated polymer gel and mixing until uniform;deaerating the film until air bubbles are removed, casting the uniformmixture on a suitable substrate; and drying the cast mixture to form afilm.

[0100] The preferred method for making an essential oil containing filmhydrates the film-forming ingredients without heating the water. Heatingthe ingredients increases energy costs in the manufacturing process.Moreover, heating results in undesirable losses of volatile ingredientsto evaporation, which also affects the germ killing activity of thecomposition due to the loss of essential oils. Further, mixing the oilsin two steps minimizes the amount of flavor lost.

[0101] While not wishing to be bound by any theories, it is believedthat the film-forming ingredients can be hydrated and mixed withoutheating due to an ionic effect known as the Donnan equilibrium.Hydrating the film-forming agents in the presence of electrolytes insolution effectively lowers the viscosity of the polymer gel beingformed, thus increasing the efficiency of the hydrating process. Thewater-soluble ingredients of the formulation provide the electrolytes,which are dissolved in the hydration solution prior to addition of thefilm-forming ingredients. High-shear mixing also accelerates hydration,which delumps the powders, providing greater surface area for watercontact. In addition, local heating effects, generated in the shearregions, provide energy for hydration without substantially raising thetemperature of the mass.

[0102] It is preferable to avoid adding both copper gluconate andsaccharin at the same time to the aqueous solution, as a precipitatewill form. Thus, it is preferred to combine sweeteners other thansaccharin with copper gluconate.

[0103] Description of Film Compositions That Deliver PharmaceuticalAgents

[0104] A second embodiment of the invention is a fast dissolving filmthat includes at least one physiologically acceptable, pharmaceuticallyactive agent. The expression “physiologically acceptable” as used hereinis intended to encompass compounds, which upon administration to apatient, are adequately tolerated without causing undue negative sideeffects. The expression encompasses edible compounds.

[0105] The expression “pharmaceutically active agents” as used herein isintended to encompass agents other than foods, which promote astructural and/or functional change in and/or on bodies to which theyhave been administered. These agents are not particularly limited;however, then should be physiologically acceptable and compatible withthe film. Suitable pharmaceutically active agents include, but are notlimited to:

[0106] A. antimicrobial agents, such as triclosan, cetyl pyridiumchloride, domiphen bromide, quaternary ammonium salts, zinc compounds,sanguinarine, fluorides, alexidine, octonidine, EDTA, and the like,

[0107] B. non-steroidal anti-inflammatory drugs, such as aspirin,acetaminophen, ibuprofen ketoprofen, diflunisal, fenoprofen calcium,naproxen, tolmetin sodium, indomethacin, and the like,

[0108] C. anti-tussives, such as benzonatate, caramiphen edisylate,menthol, dextromethorphan hydrobromide, chlophedianol hydrochloride, andthe like,

[0109] D. decongestants, such as pseudoephedrine hydrochloride,phenylepherine, phenylpropanolamine, pseudoephedrine sulfate, and thelike,

[0110] E. anti-histamines, such as brompheniramine maleate,chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate,dexchlorpheniramine maleate, diphenhydramine hydrochloride,diphenylpyraline hydrochloride azatadine meleate, diphenhydraminecitrate, doxylamine succinate, promethazine hydrochloride, pyrilaminemaleate, tripelennamine citrate, triprolidine hydrochloride,acrivastine, loratadine, brompheniramine, dexbrompheniramine, and thelike,

[0111] F. expectorants, such as guaifenesin, ipecac, potassium iodide,terpin hydrate, and the like,

[0112] G. anti-diarrheals, such a loperamide, and the like,

[0113] H. H₂-antagonists, such as famotidine, ranitidine, and the like;and

[0114] I. proton pump inhibitors, such as omeprazole, lansoprazole, andthe like,

[0115] J. general nonselective CNS depressants, such as aliphaticalcohols, barbiturates and the like,

[0116] K. general nonselective CNS stimulants such as caffeine,nicotine, strychnine, picrotoxin, pentylenetetrazol and the like,

[0117] L. drugs that selectively modify CNS function such asphenyhydantoin, phenobarbital, primidone, carbamazepine, ethosuximide,methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines,phenacemide, pheneturide, acetazolamide, sulthiame, bromide, and thelike,

[0118] M. antiparkinsonism drugs such as levodopa, amantadine and thelike,

[0119] N. narcotic-analgesics such as morphine, heroin, hydromorphone,metopon, oxymorphone, levorphanol, codeine, hydrocodone, xycodone,nalorphine, naloxone, naltrexone and the like,

[0120] O. analgesic-antipyretics such as salycilates, phenylbutazone,indomethacin, phenacetin and the like,

[0121] P. psychopharmacological drugs such as chlorpromazine,methotrimeprazine, haloperidol, clozapine, reserpine, imipramine,tranylcypromine, phenelzine, lithium and the like.

[0122] The amount of medicament that can be used in the rapidlydissolving films, according to the present invention, is dependent uponthe dose needed to provide an effective amount of the medicament.Examples of doses for specific medicaments that can be delivered per onestrip of rapidly dissolving oral film are reviewed in Table 1. TABLE 1MEDICAMENT DOSE Chlorpheniramine Maleate 4 mg. Brompheniramine Maleate 4mg. Dexchlorpheniramine 2 mg. Dexbrompheniramine 2 mg. TriprolidineHydrochloride 2.5 mg. Acrivastine 8 mg. Azatadine Maleate 1 mg.Loratidine 10 mg. Phenylephrine Hydrochloride 10 mg. DextromethorphanHydrochloride 10-20 mg. Ketoprofen 12.5 mg. Sumatriptan Succinate 35-70mg. Zolmitriptan 2.5 mg. Loperamide 2 mg. Famotidine 10 mg. Nicotine 2mg. Diphenhydramine Hydrochloride 25 mg. Pseudophedrine Hydrochloride 30mg.

[0123] The ingredients used to make the pharmaceutical containing filmsare similar to those used to make oral care films. Specifically, theplasticizing agents, cooling agents, surfactants, stabilizing agents,emulsifiers, thickening agents, binding agents, film formers,sweeteners, flavors and colors described above can also be used in allof the films according to the present invention.

[0124] The films that deliver a pharmaceutical agent can also include atriglyceride. Examples of triglycerides include vegetable oils such ascorn oil, sunflower oil, peanut oil, olive oil, canola oil, soybean oiland mixtures thereof. A preferred triglyceride is olive oil. Thetriglyceride is added to the film in amounts from about 0.1 wt % toabout 12 wt %, preferably in a range from about 0.5 wt % to about 9 wt%, of the film.

[0125] The films that contain pharmaceutical agents also can include apreservative. The preservative is added in amounts from about 0.001 wt %to about 5 wt %, preferably from about 0.01 wt % to about 1 wt % of thefilm. Preferred preservatives include sodium benzoate and potassiumsorbate.

[0126] The pharmaceutical agent containing films can also include apolyethylene oxide compound. The molecular weight of the polyethyleneoxide compound ranges from about 50,000 to about 6,000,000. A preferredpolyethylene oxide compound is N-10 available from Union CarbideCorporation. The polyethylene oxide compound is added in amounts fromabout 0.1 wt % to about 5 wt %, preferably from about 0.2 wt % to about4.0 wt % of the film.

[0127] The pharmaceutical agent containing films can also includepropylene glycol. The propylene glycol is added in amounts from about 1wt % to about 20 wt %, preferably from about 5 wt % to about 15 wt % ofthe film.

[0128] The active ingredient used in the film can be coated to mask thetaste of the active ingredient or to prevent the active ingredient fromnumbing the tongue or other surfaces in the oral cavity. The coatingsthat can be used are known to those skilled in the art. These includepolymers such, as Eudragit® E, cellulosics, such as ethylcellulose, andthe like.

[0129] An additional way to mask the taste of the active ingredient isby using an ion exchange resin such as Amberlite RP-69, available fromRohm and Haas, and Dow XYS-40010.00, available from the Dow Chemcial Co.

EXAMPLES

[0130] The invention will be illustrated in more detail with referenceto the following Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

[0131] Preparation Method I

[0132] The following method was used to prepare the films of Examples1-13.

[0133] A. The film-forming ingredients (e.g., xanthan gum, locust beangum, carrageenan and pullulan) other than Polysorbate 80 and Atmos 300are mixed and hydrated in hot purified water to form a gel and stored ina refrigerator overnight at a temperature of approximately 4° C. to formpreparation A.

[0134] B. The coloring agent(s), copper gluconate and sweetener areadded to and dissolved in purified water to form preparation B.

[0135] C. Preparation B is added to preparation A and mixed well to formpreparation C.

[0136] D. The flavoring agent and the oils (e.g., cooling agent, thymol,methyl salicylate, eucalyptol and menthol) are mixed to form preparationD.

[0137] E. The polysorbate 80 and Atmos 300 are added to preparation Dand mixed well to form preparation E.

[0138] F. Preparation E is added to preparation C and mixed well to formpreparation F.

[0139] Preparation F is poured on a mold and cast to form a film of adesired thickness at room temperature. The film is dried under warm airand cut to a desired dimension, packaged and stored.

[0140] Preparation Method II

[0141] Examples 14-18 were prepared using a preferred method, whichcomprised the following steps:

[0142] A. dissolve copper gluconate, acesulfame K, aspartame, glycerin,sorbitol and dye in purified water to form an aqueous mixture;

[0143] B. mix pullulan, xanthan gum, locust bean gum and carrageenantogether in powder form to form a powder mixture;

[0144] C. add the powder mixture from step B to the aqueous mixture fromstep A to form a hydrated polymer gel;

[0145] D. stir the hydrated polymer from step C at slow speed (about50-100 RPM) overnight at room temperature;

[0146] E. mix and dissolve cooling agent, thymol and menthol in theflavor oil;

[0147] F. add methyl salicylate, eucalyptol, Polysorbate 80 and Atmos300 to the oil mixture from step E;

[0148] G. add the oil mixture from step F to the hydrated polymer gelfrom step D and mix until uniform;

[0149] H. cast the uniform mixture from step G on a suitable backing;and

[0150] I. dry the cast mixture to form a film.

Example 1

[0151] Example 1 produced a film according to the invention having ablue-green tint, a mint odor and a refreshing mint taste.

Examples 2-4

[0152] Examples 2-4 contain sorbitol, glycerin or both. These examplesyielded products that easily broke off pieces, or were too moist and/orself-adhering. However they did produce films that rapidly dissolved inthe oral cavity with a refreshing mint taste.

Examples 5-6

[0153] Examples 5 and 6 removed glycerin and sorbitol. The resultantfilms did not stick together during processing and packaging and weremore moisture stable over a long time frame.

Examples 7-9

[0154] Examples 7-9 were produced to determine the effect of Avicel® ongerm killing activity. While Examples 7-9 produced more acceptable filmsfrom a processing and handling perspective, they had diminishedantimicrobial activity relative to films without Avicel®, such asExample 8.

Examples 10-15

[0155] Examples 10-15 varied the amounts of aspartame and menthol toalter the sweetness and coolness of the film.

Example 16

[0156] Example 16 was prepared by replacing the sorbitol replaced withmaltitol, which has less humectant properties. The resultant film wasless sticky during processing and long term storage.

Example 17

[0157] Example 17 is prepared in which pullulan is replaced with anotherfilm former, polyvinyl pyrrolidone, to produce films according to theinvention.

Example 18

[0158] Example 18 is prepared in which pullulan is partially replacedwith another film former, konjac gum, to produce films according to theinvention.

Example 19

[0159] Example 19 represents a film containing a salivary stimulant,citric acid.

Example 20

[0160] Example 20 is the film composition used in the antimicrobialefficacy studies described above.

[0161] The formulas for examples 1-20 are summarized in Table 2. Theamounts in these examples are presented as the actual weight (grams) orw/w %. These formulas create the solution/gel that is cast and driedinto a film. The actual amount of each ingredient in the finished, driedfilm depends upon the amount of relative moisture removed during drying.TABLE 2 Ex. 1 2 3 4 5 6 7 8 9 Ingredient w/w % wt (g) wt (g) wt (g) wt(g) wt (g) wt (g) wt (g) wt (g) Xanthan Gum, Food Grade 0.1070 11.6012.60 11.60 Xanthan Gum (1% solution) 3.85 3.85 3.85 3.85 3.85 LocustBean Gum, Clarified 0.2150 23.40 25.40 23.40 Locust Bean Gum (1% 7.707.70 7.70 7.70 7.70 solution) Polyvinyl Pyrrolidone Konjac GumCarrageenan 1.0730 116.60 126.10 116.60 Carrageenan (5% solution) 7.707.70 7.70 7.70 7.70 Avicel 500.00 500.00 Pullulan 51.5780 5604.006513.00 5949.00 Pullulan (25% sol) 74 74 74 74 74 Thymol NF 0.4070 0.1460.146 0.146 40.70 40.70 40.70 Methyl Salicylate NF 0.4210 0.151 0.1510.151 58.50 58.50 58.50 Eucalyptol 0.5850 0.21 0.21 0.21 42.10 42.1042.10 Menthol USP 5.8830 2.23 2.11 2.11 588.00 588.00 588.00 Mint flavor8.3640 2 3.0 3.0 836.00 836.00 836.00 Citric Acid Copper gluconate1.1150 0.275 0.41 0.14 112.00 112.00 112.00 Purified water, USP/EP 22.322 10.22 12.22 8.0 8.0 2230.00 2230.00 2230.00 Sod. saccharin USPgranulate 6.6910 1.8 1.4 1.4 2.0 2.4 Sodium saccharin 609.00 609.00609.00 Acesulfame-K Aspartame Cooling agent 0.05 0.05 0.05 13.90 13.9013.90 Maltitol Sorbitol (crystalline) 64.30 64.30 64.30 Sorbitol 70%sol. 4 4.0 Glycerin 2 2.0 136.00 136.00 136.00 Polysorbate 80 NF/EP0.5580 0.3 0.2 0.2 0.2 0.2 112.00 112.00 112.00 Atmos 300 0.5580 112.00112.00 112.00 Atlas 3000 0.3 0.2 0.2 0.2 0.2 Hi Set C Starch 77.0 FD&CGreen #3 0.0084 0.3 0.3 0.3 0.3 0.3 0.84 0.84 0.84 D&C Yellow #10 10 1112 13 14 15 16 17 18 19 20 Ingredient wt (g) wt (g) wt (g) wt (g) wt %w/w % w/w % w/w % w/w % w/w % w/w % Xanthan Gum, Food Grade 0.03850.0385 0.0385 0.0385 0.0342 0.0342 0.0342 0.04 0.04 0.34 0.0342 XanthanGum (1% solution) Locust Bean Gum, Clarified 0.077 0.077 0.077 0.0770.0684 0.0684 0.0684 0.07 0.07 0.68 0.0684 Locust Bean Gum (1% solution)Polyvinyl Pyrrolidone 16.5 Konjac Gum 5.0 Carrageenan 0.385 0.385 0.3850.385 0.342 0.342 0.342 0.34 0.34 .34 0.342 Carrageenan (5% solution)Avicel Pullan Pullan (25% sol) 18.5 18.5 18.5 18.5 16.43 16.43 16.4311.0 16.34 16.43 Thymol NF 0.146 0.146 0.146 0.146 0.130 0.13 0.13 0.130.13 0.129 0.13 Methyl Salicylate NF 0.21 0.21 0.21 0.21 0.186 0.1860.186 0.186 0.186 0.185 0.18 Eucalyptol 0.21 0.21 0.21 0.21 0.186 0.1860.186 0.186 0.186 0.185 0.18 Menthol USP 2.11 1.95 2.36 2.36 2.096 2.5202.096 2.096 2.096 2.084 2.096 Mint flavor 3.0 3.0 3.0 3.0 2.664 2.3442.664 2.664 2.664 2.649 2.0 Citric Acid 2.5 Copper gluconate 0.4 0.4 0.40.4 0.355 0.355 0.355 0.35 0.35 0.353 0.355 Purified water, USP/EP 84.2584.25 84.25 84.25 74.81 74.63 74.81 75 75 74.39 72.2168 Sod. saccharinUSP granulate Sodium saccharin Acesulfame-K 0.5 0.5 0.5 0.5 0.444 0.4440.444 0.45 0.45 .04420 0.444 Aspartame 1.30 1.60 1.30 1.60 1.421 1.4211.421 1.4 1.4 1.413 1.421 Cooling agent 0.10 0.10 0.10 0.10 0.089 0.0890.089 0.089 0.089 0.088 0.89 Maltitol 2.80 Sorbitol (crystalline)Sorbitol 70% sol. 0.199 Glycerin 0.418 Polysorbate 80 NF/EP 0.4 0.4 0.40.4 0.355 0.355 0.355 0.355 0.355 0.353 0.355 Atmos 300 0.355 0.3550.355 0.355 0.355 0.353 0.355 Atlas 3000 0.4 0.4 0.4 0.4 Hi Set C StarchFD&C Green #3 0.003 0.003 0.003 0.003 0.0026 0.0026 0.0026 0.0026 0.0026D&C Yellow #10

[0162] The following examples are films according to the secondembodiment of the present invention, in which the rapidly dissolvingfilm contains a pharmaceutical agent. Examples 21A-21E, listed in Table3, are medicament containing rapidly dissolvable oral film formulas. Theamounts in Table 3 are in milligrams. TABLE 3 Example Number 21A 21B 21C21D 21E Dextromethorphan HBr 7.500 Phenylepherine HCI 10.0000 10.0000Chlorpheniramine 4.0000 Maleate Loperamide HCI 2.0000 Nicotine 2.0000Xanthan Gum 0.0818 0.0818 0.0818 0.0818 0.0818 Locust Bean Gum 0.09540.0954 0.0954 0.0954 0.0954 Carrageenan 0.4088 0.4088 0.4088 0.40880.4088 Pullulan 21.8036 21.8036 21.8036 21.8036 21.8036 Sodium Benzoate0.0954 0.0954 0.0954 0.0954 0.0954 Acesulfame Potassium 0.6814 0.68140.6814 0.6814 0.6814 Salt Aspartame NF 1.9078 1.9078 1.9078 1.90781.9078 Purified Water * * * * * Cooling agent 0.1363 0.1363 0.13630.1363 0.1363 Menthol 2.7255 2.7255 2.7255 2.7255 2.7255 Polysorbate 80NF 0.4770 0.4770 0.4770 0.4770 0.4770 Atmos 300 0.4770 0.4770 0.47700.4770 0.4770 Propylene Glycol 4.0882 4.0882 4.0882 4.0882 4.0882 OliveOil 0.6814 0.6814 0.6814 0.6814 0.6814 Titanium Dioxide 0.3407 0.34070.3407 0.3407 0.3407 Total Dose Weight 41.5000 44.0000 48.0000 36.000036.0000

[0163] Table 4 summarizes additional films according to the presentinvention. The amounts in Table 4 are % w/w prior to drying. TABLE 4Examples 22A 22B 22C 22D 22E 22F 22G 22H 22I Xanthan Gum .03 .03 .06 .03.03 .03 .06 .06 .06 Locust Bean .07 .07 .07 .07 .07 .07 .07 .07 .07 GumCarrageenan 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Pullulan 16.0 16.0 16.016.0 16.0 16.0 16.0 16.0 16.0 Sodium 0.1 0.1 0.1 .07 .07 .07 .07 .07 0.7Benzoate Acesulfame 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 PotassiumAspartame 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 Water qs100 qs100 qs100Qs100 qs100 qs100 qs100 qs100 Qs100 Cooling agent 0.1 0.1 0.1 0.1 0.10.1 0.1 0.1 0.1 Menthol 2.0 2.0 2.0 1.3 2.0 2.0 2.0 2.0 2.0 Polysorbate80 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Atmos 300 0.35 0.35 0.350.35 0.35 0.35 0.35 0.35 0.35 Propylene 1.0 1.0 1.0 1.0 1.0 1.0 3.0 3.03.0 Glycol Peg 1450 — 3.10 — — — — — — — Olive Oil — — — 1-2 2.0 2.0.5-2 — .5 Polyox N-10 — — — — — — — — 1.0 Titanium — 0.25 0.25 0.25 0.25— 0.25 — 0.25 Dioxide

[0164] Example 22A was used to make films containing a) 7.5 mg ofdextromethorphan hydrobromide, b) 2.5 mg of tripolidine, c) 4.0 mg ofchlorpheniramine maleate and d) 12.5 mg of diphenhydraminehydrochloride.

[0165] Example 22B was used to make a film containing 10 mg ofdextrometorphan hydrobromide.

[0166] Example 22C was used to make a film containing 10 mg ofdextromethorphan hydrobromide.

[0167] Example 22D was used to make a film containing a) 10 mg ofphenylepherine hydrochloride, b) 10 mg of phenylepherine hydrochlorideand 4 mg of chlorpheniramine maleate and c) 10 mg of dextromethorphanhydrobromide.

[0168] Example 22E was used to make a film containing 7.5 mgdextromethorphan hydrobromide.

[0169] Example 22F was used to make a film containing 20 mg of coateddextromethorphan hydrobromide to provide a 7.5 mg dose.

[0170] Example 22G was used to make a film containing a) 7.5 mgdextromethorphan hydrobromide, b) 10 mg phenylepherine hydrochloride andc) 10 mg phenylepherine hydrochloride and 4 mg chlorpheniramine maleate.

[0171] Example 22H was used to make a film containing 15 mg ofdextromethorphan hydrobromide.

[0172] Example 22I was used to make a film containing 15 mg ofdextromethorphan hydrobromide.

[0173] Processes For Making Pharmecutical Containing Films

[0174] Example 22A was made using the following procedure.

[0175] 1. Add the sodium benzoate and sweeteners to water.

[0176] 2. Mix the locust bean gum, xanthan gum and carrageenan together.

[0177] 3. Add the gum mixture to the mixture of step 1 and mix untildissolved.

[0178] 4. Mix the active ingredient with either water or propyleneglycol. Heat if needed.

[0179] 5. Add the remaining ingredients to the mixture of step 4 or mixthe remaining ingredients in a separate mixture.

[0180] 6. Add the mixtures of step 4 and step 5 to the mixture of step3. Cast and dry to make a film and cut to a size to achieve the desireddose.

[0181] Examples 22B-22E were made using the following procedure.

[0182] 1. Add the sodium benzoate to water heated to 50 C. Mix todissolve.

[0183] 2. Separately, add the Peg 1450, titanium dioxide and activeingredient to the mixture of step 1, mixing with each addition.

[0184] 3. Mix the locust bean gum, xanthan gum and carrageenan together.

[0185] 4. Add the gums to the mixture of step 2 and mix until dissolve.

[0186] 5. Add the remaining ingredients together with heat if needed.

[0187] 6. Add the mixture of steps 4 and 5 together. Cast and dry tomake a film and cut to a size to achieve the desired dose.

[0188] Examples 22F-22I were made in the same manner as Examples 20B-20E, except the active was dispersed right before the film was cast.

[0189] While the invention has been described in detail and withreference to specific examples thereof, it will be apparent to oneskilled in the art that various changes and modifications can be madetherein without departing from the spirit and scope thereof.

What is claimed is:
 1. A consumable film adapted to adhere to anddissolve in a mouth of a consumer, wherein said film comprises at leastone water soluble polymer and an antimicrobial effective amount of atleast one essential oil selected from the group consisting of thymol,methyl salicylate, eucalyptol and menthol.
 2. The consumable filmaccording to claim 1, comprising at least two of said essential oils. 3.The consumable film according to claim 1, comprising at least three ofsaid essential oils.
 4. The consumable film according to according toclaim 1, comprising thymol, methyl salicylate, eucalyptol and menthol.5. The consumable film according to claim 4, further comprising a saltof gluconic acid.
 6. The consumable film according to claim 4, furthercomprising copper gluconate.
 7. The consumable film according to claim1, wherein said water soluble polymer is selected from the groupconsisting of pullulan, hydroxyproplymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol,tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl polymer, amylose, highamylose starch, hydroxypropylated high amylose starch, dextrin, pectin,chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soyprotein isolate, whey protein isolate, casein and mixtures thereof. 8.The consumable film according to claim 7, wherein said water solublepolymer is pullulan.
 9. The consumable film of claim 8, comprising:about 40 to about 80 wt % pullulan; about 0.01 to about 4 wt % thymol;about 0.01 to about 4 wt % methyl salicylate; about 0.01 to about 4 wt %eucalyptol; and about 0.01 to about 15 wt % menthol.
 10. The consumablefilm according to claim 7, further comprising: about 0.01 to about 5 wt% of at least one stabilizing agent; about 0.001 to about 0.1 wt % of atleast one of at least one coloring agent; about 0.1 to about 8 wt % ofwater; about 0.1 to about 15 wt % of at least one sweetening agent;about 0.1 to about 15 wt % of at least one flavoring agent; about 0.1 toabout 4 wt % of at least one cooling agent; and about 0.1 to about 5 wt% of at least one surfactant.
 11. The consumable film according toaccording to claim 10, wherein said least one stabilizing agent isselected from the group consisting of xanthan gum, locust bean gum andcarrageenan, and said at least one sweetening agent is selected from thegroup consisting of saccharin, aspartame and acesulfame K.
 12. Theconsumable film according to claim 1, wherein said film does notsubstantially adhere to itself.
 13. The consumable film according toclaim 1, wherein said film is free of glycerin and sorbitol.
 14. Theconsumable film according to claim 1, wherein said film is free ofhumectants.
 15. The consumable film according to claim 1, wherein theessential oils comprises at least about 10 wt % of the film.
 16. Theconsumable film according to claim 15, wherein the essential oilscomprises at least about 15 wt % of the film.
 17. The consumable filmaccording to claim 1, further comprising water in an amount from about 3wt % to about 8 wt %.
 18. A method for preparing a physiologicallycompatible film, said method comprising: mixing at least one watersoluble film former and at least one stabilizing agent to provide afilm-forming mixture; dissolving water-soluble ingredients in water toprovide an aqueous solution; combining said film-forming mixture andsaid aqueous solution to provide a hydrated polymer gel; mixing oils toform an oil mixture; adding said oil mixture to said hydrated polymergel and mixing to provide a uniform gel; casting the uniform gel on asubstrate; and drying the cast gel to provide said film.
 19. The methodaccording to claim 18, wherein at least one surfactant is mixed intosaid oil mixture.
 20. The method according to claim 18, wherein thetotal amount of said oils in said oil mixture is at least about 5 wt %of the total weight of ingredients in said method.
 21. The methodaccording to claim 20, wherein said total amount of oils is at leastabout 15 wt %.
 22. The method according to claim 18, wherein said dryingis conducted until said film has a moisture content of about 3 wt % toabout 8 wt %.
 23. The method according to claim 18, wherein, prior tobeing combined with said aqueous solution, said film-forming mixture ishydrated with water at a temperature of about 25 to about 50° C. andsubsequently chilled to a temperature of about 4 to about 30° C. forabout 2 to 48 hours.
 24. The method according to claim 18, wherein saidfilm-forming mixture is a powder, which is directly combined with saidaqueous solution.
 25. The method according to claim 24, wherein saidhydrated polymer gel is formed without heating.
 26. The method accordingto claim 25, wherein said hydrated polymer gel is stirred at roomtemperature for about 2 to about 48 hours.
 27. The method according toclaim 26, wherein said oil mixture is prepared by mixing thymol andmenthol in a flavor oil, and subsequently adding methyl salicylate andeucalyptol.
 28. A non-self-adhering film produced according to themethod of claim
 18. 29. The method according to claim 18, wherein thewater soluble film former is selected from the group consisting ofpullulan, hydroxyproplymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium alginate, polyethylene glycol, tragacanth gum,guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylatecopolymer, carboxyvinyl polymer, amylose, high amylose starch,hydroxypropylated high amylose starch, dextrin, pectin, chitin,chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy proteinisolate, whey protein isolate, casein and mixtures thereof.
 30. Themethod according to claim 29, wherein said water soluble polymer ispullulan.
 31. A consumable film adapted to dissolve in the mouth of aconsumer, wherein said film comprises a single layer including pullulanand at least one pharmaceutical agent.
 32. The consumable film accordingto claim 31, wherein said pharmaceutical agent is selected from thegroup consisting of antimicrobial agents, non-steroidalanti-inflammatory agents, anti-tussives, decongestants, anti-histamines,expectorants, anti-diaherrals, H₂-antagonists, proton pump inhibitors,central nervous system agents, analgesics, and mixtures thereof.
 33. Theconsumable film according to claim 32, wherein the antimicrobial agentis selected from the group consisting of triclosan, cetyl pyridiumchloride, domiphen bromide, quaternary ammonium salts, zinc compounds,sanguinarine, fluorides, alexidine, octonidine, EDTA and mixturesthereof.
 34. The consumable film according to claim 32, wherein thenon-steroidal anti-inflammatory agent is selected from the groupconsisting of aspirin, acetaminophen, ibuprofen, diflunisal, fenoprofencalcium, naproxen, tolmetin sodium, indomethacin, and mixtures thereof.35. The consumable film according to claim 32, wherein the anti-tussiveis selected from the group consisting of benzonatate, caramiphenedisylate, dextromethorphan hydrobromide, chlophedianol hydrochlorideand mixtures thereof.
 36. The consumable film according to claim 32,wherein the decongestant is selected from the group consisting ofpseudoephedrine hydrochloride, phenylepherine, phenylpropanolamine andmixtures thereof.
 37. The consumable film according to claim 32, whereinthe anti-histamine is selected from the group consisting ofbrompheniramine maleate, chlorpheniramine maleate, carbinoxaminemaleate, clemastine fumarate, dexchlorpheniramine maleate,diphenhydramine hydrochloride, diphenhydramine citrate, diphenylpyralinehydrochloride, doxylamine succinate, promethazine hydrochloride,pyrilamine maleate, tripelennamine citrate, triprolidine hydrochlorideand mixtures thereof.
 38. The consumable film according to claim 32,wherein the expectorant is selected from the group consisting ofguaifenesin, ipecac, potassium iodide, terpin hydrate and mixturesthereof.
 39. The consumable film according to claim 32, wherein theanti-diarrheal is loperamide.
 40. The consumable film according to claim32, wherein the H₂-antagonist is selected from the group consisting offamotidine, ranitidine and mixtures thereof.
 41. The consumable filmaccording to claim 32, wherein the proton pump inhibitor is selectedfrom the group consisting of omeprazole, lansoprazole, and mixturesthereof.
 42. A method for delivering and enhancing the retention of aneffective amount of an antimicrobial agent to the oral cavity comprisingintroducing in the oral cavity a rapidly dissolving film comprisingpullulan and an antimicrobial agent comprising menthol and at least oneof methyl salicylate, eucalyptol and thymol, wherein said pullulanenhances the retention of the antimicrobial agent in the oral cavity.43. The method according to claim 42, wherein the antimicrobial agentcomprises menthol, methyl salicylate, eucalyptol and thymol.
 44. Themethod according to claim 42, wherein the amount of pullulan in the filmis from about 40 wt % to about 80 wt %.
 45. The method according toclaim 42, wherein the amount of antimicrobial agent in the film is fromabout 5 wt % to about 12 wt %.
 46. The method according to claim 43,wherein the amount of antimicrobial agent in the film is from about 5 wt% to about 12 wt %.
 47. A method for delivering and enhancing theretention of an effective amount of an antimicrobial agent to the oralcavity comprising introducing in the oral cavity the consumable filmaccording to claim 9.